Rationale

Fragile X syndrome (FXS), the most prevalent genetic form of intellectual disability, is characterized by intellectual impairment, impaired sociability, aggression, self-injury, hyperactivity, and attention deficits. A consequence of the hyperactivity and attention deficits is that individuals with FXS are frequently diagnosed with attention deficit hyperactivity disorder (ADHD) and treated with medications approved for ADHD (e.g., the α₂-agonist clonidine). The pharmacotherapy of FXS is often accompanied with behavioral therapies that rely on positive reinforcement and other operant principles. Despite the commonplace mixture of drug and behavioral therapy, little attention has been paid to the observation that clonidine or other psychotropic drugs may alter operant processes.

Objectives

In the present progressive ratio study, we used a knockout mouse model to test the effects of the fragile X genotype, the α₂-agonist clonidine, and the fragile X genotype and clonidine together on operant processes in a positive reinforcement task.

Results

We found that clonidine decreased the progressive ratio breakpoint, increased the length of post-reinforcement pauses, and slowed the run rate. None of these effects varied by genotype. The effect on breakpoint suggests that clonidine alters motivation, but analysis using mathematical principles of reinforcement (MPR) did not rule out motor parameters as a contributor.

Conclusions

Our findings show that clonidine alters operant behavior and serve as a caution for combining clonidine with behavioral therapies that rely on positive reinforcement. Further research using different murine behaviors (e.g., touchscreen tasks) or different animal models (e.g., knockout rats) is needed to explore the interaction between pharmaco- and behavioral therapy.

中文翻译：

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可乐定对Fmr1基因敲除小鼠进行性比率计划性能的影响

基本原理

脆性X综合征（FXS）是智力障碍的最普遍遗传形式，其特征是智力障碍，社交能力受损，攻击性，自残，多动和注意力缺陷。多动和注意力缺陷的一个后果是，与FXS的个体常常诊断为注意力缺陷多动障碍（ADHD），并批准了ADHD（例如，α药物治疗₂激动剂可乐定）。FXS的药物治疗通常伴随着依靠积极强化和其他操作原则的行为疗法。尽管将药物和行为疗法混为一谈，可乐定或其他精神药物可能会改变手术过程，这一点很少引起注意。

目标

在本渐进比的研究中，我们使用的敲除小鼠模型来测试脆性X基因型的影响，α ₂受体激动剂可乐定，和脆性X基因型和可乐定一起操作性过程在正强化任务。

结果

我们发现可乐定降低了进行性比率的断点，增加了补强后停顿的时间，并减慢了运行速度。这些影响均未因基因型而异。对断点的影响表明可乐定会改变动机，但使用增强数学原理（MPR）进行的分析并未排除运动参数的影响。

结论

我们的研究结果表明，可乐定可改变操作者的行为，并在将可乐定与依赖于积极强化的行为疗法相结合时提供警告。需要进一步研究使用不同的鼠类行为（例如，触摸屏任务）或不同的动物模型（例如，敲除大鼠）来探索药物和行为疗法之间的相互作用。